This invention relates to PLA.sub.2 inhibitors. In one aspect, this invention relates to a method of inhibiting PLA.sub.2 using the PLA.sub.2 inhibitors of the invention. In another aspect, this invention relates to a method of inhibiting calcium-independent PLA.sub.2 using the PLA.sub.2 inhibitors of the invention.
Phospholipases A.sub.2 are a diverse group of esterases which specifically hydrolyse the sn-2 ester of membrane and other phospholipids. Both calcium dependent and independent examples are known. These enzymes are principally responsible for the release of arachidonic acid during signal transduction in mammalian cells. As such their modulation and inhibition are of potential therapeutic value in treating many diseases and conditions where arachidonic acid, lysophospholipids, and their metabolites (prostaglandins, leukotrienes, thromboxanes, platelet activating factor, etc.,) are responsible for the deleterious effects of these conditions and diseases.
In some circumstances it may be beneficial to inhibit more than one phospholipase A.sub.2, particularly in cases where inhibition of the production of early as well as late mediators can be important in controlling pathology, or where inhibition of signalling events can be combined with inhibition of release of arachidonic acid stores. ##STR3##
Evidence has accumulated for a potential role of PLA.sub.2 in myocardial injury to the ischemic heart.
Lysophospholipids have also been implicated as potential mediators of sudden cardiac death, Corr et al, "Lethal Arrhythmias Resulting from Myocardial Ischemia and Infarction", Rosen & Patti, eds., Kluwer Academic Publishers, Boston, 91-014 (1989). The addition of lysophospholipids to normoxic myocardial tissue in vitro induces electrophysiological alterations that are similar to those observed in the ischemic heart in vivo Corr et al, Circ. Res, 55, 135-54 (1984).
Most importantly, lysophospholipid accumulation in the ischemic dog heart in vivo has been correlated with the frequency of cardiac arrhythmias, Kinnaird et al, Lipids, 23, 32-35 (1988). Furthermore, it is known that the carnitine acyltransferase 1 inhibitor, 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (POCA), prevents the onset of ventricular fibrillation and ventricular tachycardia and inhibits the accumulation of lysophospholipids (and long-chain acylcarnitines) in the ischemic cat heart in vivo, Corr et al, J. Clin. Invest., 83, 927-36 (1989).
Accelerated phospholipid catabolism by PLA.sub.2 has also been implicated as a cause of infarct damage in the ischemic heart. In the ischemic heart, ATP levels decrease. Treatment of rat neonatal myocytes with the glycolytic inhibitor iodoacetate lowers the levels of ATP which results in the release of arachidonic acid and morphological alterations of the myocytes, Chien et al, J. Clin. Invest., 75, 1770-80 (1985). One PLA.sub.2 inhibitor (U26,384) prevented the release of arachidonic acid, phospholipid degradation, sarcolemmal membrane defects and the release of creatine kinase that was induced by the treatment of rat neonatal myocytes with iodoacetate, Sen et al, J. Clin. Invest., 82, 1333-38 (988).
LTB.sub.4 is an arachidonic acid metabolite which is produced by the 5-lipoxygenase pathway. Pharmacologically, LTB.sub.4 is an important mediator of inflammation. LTB.sub.4 is known to induce chemotaxis, chemokinesis, aggregation, and degranulation of leukocytes in vitro, and to induce accumulation of polymorphonuclear leukocytes, and increase vascular permeability and edema formation in vivo. Particularly high levels of LTB.sub.4 are detected in lesions in inflammatory diseases such as rheumatoid or spondylarthritis, gout, psoriasis, ulcerative colitis, Crohn's disease, multiple sclerosis and some respiratory diseases. Since the compounds herein inhibit PLA.sub.2 and thereby LTB.sub.4 synthesis, the compounds of the present invention are useful in treating inflammatory conditions in mammals such as rheumatoid arthritis, inflammatory bowel disease, psoriasis and the like.
Therefore, compounds which inhibit PLA.sub.2 provide potential therapeutic approaches to the prevention of arrhythmia, infarct damage, sudden death, and inflammatory conditions, i.e., conditions mediated by inflammatory mediators such as prostaglandins and leukotrienes.